How Dietary Restriction Works

Important facts to remember

In the 1920s, the early days of research into the effect of dietary restriction on life extension, it was thought by pioneers of this method, such as Clive McCay of Cornell University, that the increase seen in life span was due to a slowing down of the maturing process, and/or by a slowing of the rate of growth. This is now known not to be the case, since adult animals placed on dietary restriction have regularly achieved lengthened life spans with no signs at all of delayed maturity (because they were already mature when the diet began).

Other theories have suggested that reduction in excess body weight, resulting from dietary restriction, could account for longevity. This, too, is now seen to be inaccurate, since in free feeding animals there is no connection between the amount of body fat the animal has and its life expectancy and, as shown by the research referred to in the previous chapter, those animals which achieve increased life span by dietary restriction are in fact the heavier animals. Weindruch and Walford elaborate on this fact by pointing out that when rats are kept slim by exercise, no increase in their maximum life span is seen, but when animals are kept at a similar weight level to that achieved by exercise, by using dietary restriction, there is indeed an increased life span.

Incidentally, this highlights a repetitive finding in research, that exercise has little if any effect on life expectancy, even though it certainly does influence overall well-being.

These major researchers ask us to keep a few very important facts in mind as we consider how dietary restriction works. The first is that calorie restriction (as part of an otherwise optimal diet) achieves its results in practically all species tested to date, whether cows, fruit flies, mosquitoes, rats, mice or protozoans (and of course humans if we accept the results of the Okinawa experience as evidence from a self-generated trial). In all these creatures one indicator is constant: as dietary restriction continues so is there a reduction in accumulations of the fat/protein complex lipofuscin (see Chapter 3 for comments on the build-up of age pigments in cells with age). As an increase of lipofuscin in cells is seen as a major sign of accelerating aging, and as a reduction in its presence occurs in ALL species to which dietary restriction is applied, and as a ‘side-effect’ of dietary restriction is life extension, the removal or reduction of lipofuscin is of some considerable importance in understanding the mechanisms involved.

We are also asked to consider the connection, or lack of it, between life extension and benefits to the immune system (achieved by dietary restriction), important as this may be. The reason for dismissing the idea that improvements in immune function are central to the life extension process is because creatures such as protozoa have no immune systems, and yet they, like all other creatures to which dietary restriction is applied respond by living longer.

Reducing disease incidence in itself, does not seem to have much effect on increasing Life expectancy overall, and so improving immune function seems not to be involved in life extension. As Weindruch and Walford point out, a number of other dietary strategies such as protein restriction, can dramatically cut down incidence of auto-immune diseases (chronic nephropathy in rats, for example) but this hardly contributes at all to an increase in life span in animals so treated. The message they repeat is that only calorie restriction achieves life extension in mammals.

Is appearing more youthful the same as life extension?

It is important to remind ourselves that life extension does not necessarily mean the same thing as looking younger, or having a more youthful immune system, or a more efficient ability to synthesize proteins. Such features are important, of course, but they do not automatically lead to life extension, although they may well accompany it when it is achieved. The significance of this thought will become more apparent when we look at other methods being tried in the quest for life extension, including use of growth hormone (see Chapter 7). For, while growth hormone stimulation, or its actual injection into the body, has a ‘youthening’ effect on animals and humans, as yet there is no evidence of it affecting the length of life.

There is a distinction to be made, therefore, between methods which make us feel (and perhaps look) younger but don’t actually extend life span, and those which may not have this particular effect but which do improve our potential longevity.

The evolution factor

Weindruch and Walford quote the work of Dr J. Totter, who has suggested that there is an evolutionary process at work when dietary restriction is operating (either in natural settings or experimentally). Dr. Totter believes that when there exists a scarcity of food, energy is diverted from reproductive functions and basic metabolic activity, towards muscular activity, in order to enhance the chances of survival as food is sought. When food is freely available again, breeding (reproduction) is resumed and the basic metabolic rate increases.

There is evidence in human populations to support this hypothesis, and as Weindruch and Walford point out: ‘It makes good evolutionary sense not to have babies when food is scarce, to divert reproductive energy to personal survival, and to outlive scarcity.’ What makes even more evolutionary (survival of the species) sense, they maintain, is the fact that dietary restriction seems to have a rejuvenating effect on reproductive function, but only once food is again freely available. They point to what happens to rats following 10 weeks of a 50 per cent reduction in calorie intake. Young animals cease their menstrual cycles during the dietary restriction period (evidence of diversion of energy to muscular activity away from reproductive function?) and resume their cycles and ability to reproduce when full feeding is restored. More remarkable still is the effect on animals who have already ceased their cycles due to age, and who are found, after a 50 per cent calorie restriction for ten weeks (once full feeding is restarted), to recommence menstruating and to become fertile once more.

What happens to basic metabolic rate during dietary restriction?

In general, the more energy used to maintain body functions, in relation to body weight, the shorter the life expectancy of the organism. In other words, the better the energy efficiency the greater will be life expectancy.

As we have seen, in numerous examples, the single most important feature of dietary restriction is not fat, or protein, or carbohydrate restriction, nor additions of particular nutrients, but quite simply calorie restriction combined with a diet adequate in all other respects. This means that life extension is achieved when we modify energy intake, which must also mean that, in any search for how life extension techniques work, we must look closely at the energy mechanisms of the body.

The possibilities are many. Dietary restriction could reduce the metabolic rate, slowing down the function of energy consumption, i.e we could ‘burn’ less. Or it could be that the efficiency with which the organism handles energy improves when dietary restriction is operating. It might also be that there are fewer free radicals generated when dietary restriction is applied, since these rogue molecules are a by-product (amongst other things) of energy production processes involving oxygen; or it might be that the toxic by-products of oxygen are better dealt with during dietary restriction. Or perhaps all of these things happen to the benefit of the organism when calorie (energy) intake is reduced.

How much energy do you use?

A distinction is made between energy production in the mitochondria (a cell’s energy source) which takes place in muscle and that which takes place anywhere else in the body (non muscle). From the aging viewpoint it is known that total energy consumption, as well as muscular energy consumption declines with age. Muscular energy use accounts for around a third of the energy used when we are at rest, and upwards of 90 per cent of energy used during heavy activity. The overall decline seen when we (or animals) age is therefore probably because muscle mass also declines with age, by around 3.5 per cent every 10 years. Quite simply less muscle uses less energy. With advanced age, however, energy consumption by non-muscle tissue (organs, brain etc.) increases, and this is thought to relate to the development of diseases affecting these areas (cardiovascular problems, cancers etc.).

At age 30 our non-muscle energy consumption amounts to around 38 per cent of our total energy use on average, but by the age of 80 this will have risen to over 50 per cent of energy use. Dr Totter, whose evolutionary ideas have been already referred to, believes that energy consumption by non-muscular tissues (in reproductive processes as well as organ function) are potentially harmful because this is, as he puts it: ‘The main sources of oxygen (free) radicals that maybe the direct cause of aging.’ Most muscular energy consumption is not regarded by Totter as producing free radical activity, and Weindruch and Walford remind us that evidence to date in longevity research has shown that active exercise has little or no effect on life span, which supports the idea that muscle metabolism is not much involved in the ageing process.

They have evaluated the research to date on the vital state of mitochondria (the energy producing unit of the cell) and conclude that it may not be possible to point to them as having a direct relation to the aging process, but that since they are continually being replaced as they become inefficient through wear and tear, this ‘provides an endless source of active oxygen which can attack other critical parts of the cell’

Free radicals and the ageing process

In Chapter 8 I give a detailed account of the connection between free radicals and ageing, the so-called ‘rusting’ theory. Free radicals are certainly part of the energy production scene and need to be understood in this context as well as the more general setting of their influence on the rest of the body.

All atoms carry electrical entities, protons (positively charged) and electrons (negatively charged), and these are in orbit around the nucleus of the cell. When atoms combine to form molecules it is through a balanced linking of these various electrical potentials, leaving a neutral (electrically speaking) end product. However, in some instances an unpaired electron remains spinning in orbit around the atom or molecule, ready to latch on to any passing atom or molecule to which it can attach itself. When this happens it will break existing bonds, destroying the electrical links of previously balanced molecules or atoms, a process which happens when oils or fats go rancid or oxidize in the presence of the oxygen in air. Energy is released in the process, and a chain reaction of more combustion or damage continues as the newly formed, damaged, molecules continue the process of grabbing electrons wherever they can. So a free radical is an unbalanced (electrochemically speaking) unpaired atom, or particle of a molecule (itself a combination of atoms), which is desperately seeking an electron with which it can link via its ‘free’ attachment site.

Atoms ‘hold’ on to each other, or link, just as hydrogen and oxygen atoms combine to form water, for example. When water is formed, two hydrogen atoms are joined electrically to one oxygen atom, giving us the formula H2O for the fairly stable water molecule. When two hydrogen atoms link, however, to two oxygen atoms, an unstable molecule of H2O2 – hydrogen peroxide – is formed, and everyone knows what bleach can do to hair when its rampant free radicals touch it.

The processes of linking and breaking of molecules are constant features of all of life’s activities, with enzymes acting as catalysts to allow the joining and unjoining of atoms and molecules to occur smoothly. When something burns or rusts it is because of the activity of unlinked atoms or molecules which have a tendency to latch onto other molecules, damaging in the process by removing one of their electrons. This is what happens when metal rusts, rubber perishes, a sliced apple turns brown when exposed to air, fats go rancid or hair is bleached . . . and so on.

Protection from antioxidants

We live in an oxygen-rich environment, in which there are
abundant opportunities for exposure to oxidative stress, and this is particularly true of body cells where oxygen is part of the energy production cycle. Damage to cell membranes (or their fat content) and other key parts of the cell, including the genetic material (DNA, RNA) itself is possible, unless a variety of valuable protective molecules (such as enzymes, and vitamins A, C and E) act to contain and control free radicals by use of their antioxidant abilities. This is why lemon juice (vitamin C) squeezed onto a sliced apple prevents browning from taking and why vitamin E prevents fats and oils from oxidizing. Some people are better endowed with antioxidant protectors than others (a lot to do with their diets) and some people produce free radicals far more freely than do others.

How much antioxidant (protective) potential is present and how great a need there is for it, are the key elements which decide how much free radical damage will result, and the extent of disease and dysfunction that will follow. Many major chronic diseases, often associated with ageing, are now thought to be largely the result of free radical activity, including arterial disease (atherosclerosis) and cancer.

Are you a ‘burner’ or are you ‘thrifty’?

Weindruch and Walford have dubbed some people (and animals)
‘burners’ and others ‘thrifty’ since they believe, and give ample evidence to support the idea, that the efficiency with which mitochondria produce the substance ATP (adenosine triphosphate, from which the body derives its energy) varies
greatly from person to person, and from animal to animal.
Although the degree of efficiency is probably genetically
determined, it is seen to improve somewhat with dietary
restriction (and with antioxidant nutrition).

Those people (and animals) who are somewhat ‘sloppy’ and inefficient in their energy production activity, and who release an undue amount of heat and possibly free radicals in the process, are termed ‘burners’. While those who efficiently transfer raw materials (food) into ATP, with little wastage in terms of heat or free radical activity, are called ‘thrifty’.

It is important to remember that the more efficient the energy production, and the fewer free radicals emerging from the process, the greater the tendency for a longer life span. And since dietary restriction seems to encourage a ‘thriftier’ level of energy production, there seems little doubt that life extension is at least partly the result of improved energy production efficiency and lower free radical activity.

Weindruch and Walford summarize their findings in this important area by listing the characteristics, which they feel their experience allows them to predict, in relation to ‘thrifty’ and place, ‘burner’ mice (they see no reason why these same findings should not apply to humans). They predict that the thriftiest 20 per cent of a group of 100 mice (or people) to whom dietary restriction is applied will be those with the highest body weights while on the dietary restriction programme.

The ‘thrifty’ mice (people) will have:

• a longer life span
  
• higher body weights (during and after, but not necessarily before dietary restriction)
  
• lower oxygen consumption
  
• lower body temperature
  
• fewer signs of ageing
  
• less free radical activity
  

The most likely ‘burner’ mice (people) would be the 20 per cent of this group with the lowest body weights during dietary restriction, and they would have all these characteristics in reverse.

It is clear that an ‘efficient’ (thrifty) organism will make the most of the limited food it receives on a restriction programme, and will demonstrate this by maintaining body weight throughout the regime, whereas an ‘inefficient’ (burner) organism would lose weight and become relatively slim when restricted.

Weindruch and Walford point out that animals become ‘thriftier’ in their use of energy when on dietary restriction, and that they continue to be thrifty afterwards. One of the major findings in life extension research has been the revelation that core body temperature drops with dietary restriction. The warmer the environmental temperature the less energy the organism (fruit fly, mouse or human) has to generate and expend in order to produce adequate body temperature. Just what effect the external environmental temperature has on the benefits or otherwise of dietary restriction and life extension I cover in Chapter 9.

Making protein

The manufacture of new protein by cells is seen to decline steadily with advancing age, but whether this is because of relative changes in the efficiency of DNA/RNA activity is not certain. One of the features seen during dietary restriction is that of a more efficient synthesis by cells of protein. There is disagreement between experts on whether this improved synthesis of protein is simply a sign of increased youthfulness following (or accompanying) dietary restriction, or whether it is actually a part of the process which produces life extension. One argument which supports the idea that this might be an actual cause of the life extension phenomenon is that it is now known that the changes in protein synthesis (when dietary restriction is applied) are not uniform, they are selective. That is to say some proteins are produced very much more efficiently and abundantly, while at the same time all other proteins are synthesized at only a moderately increased rate, during dietary restriction.

For example, a particular protein called EF-1 (‘elongation factor’) is seen to be increased dramatically with dietary modification, and this particular protein is known to decline in efficient production before general signs of ageing occur (such as an overall drop in protein synthesis) in a variety of species. Some of these protein synthesis changes might be the result of more RNA being produced (the template sent from the DNA blueprint in the cell nucleus to show the cell what protein to make), or might it simply be the case that the messenger RNAs start binding more efficiently with ribosomes to form new proteins?

Weindruch and Walford believe that there are strong arguments in support of the idea that some of the genes in DNA, which are specifically linked to the ageing process, are affected beneficially by dietary restriction. Some of these help immune function while others are related to improving oxidation protection functions as well as the elongation factor mentioned above.

DNA looks after itself

Part of this selective upgrading of certain functions, during
dietary restriction, seems to be the way in which DNA makes
sure that it is itself protected more efficiently (for example, ensuring repair where damage has occurred) especially in those sites where genes exist which influence ageing. In this way dietary restriction causes DNA to produce more ‘physiologically useful’ messenger RNAs and, in short-lived, disease-prone breeds of animals, to produce fewer cancer-initiating RNA messengers. Both of these effects will increase life expectancy.

What about immune function and hormones?

Chapter 7 looks at the remarkable ‘youth enhancing’ results obtained by the use of growth hormone, and I also elaborate on other hormonal theories of aging. At this point I suggest that we should note simply that dietary restriction and fasting change hormonal patterns beneficially, and that the overall effect of a better functioning hormonal system makes for a healthier and
better balanced individual (animal or human), with ‘younger’
characteristics, but not necessarily with a longer life expectancy. This is much the same point as made in relation to the immune system, which becomes increasingly efficient with dietary restriction (and fasting). This effect is bound to increase life expectancy simply by keeping disease processes under better control (or by helping to avoid them altogether). However, this is not the same as saying that enhanced immune function (whether resulting from dietary restriction or anything else) produces life extension.

For example, where immune function has been made more efficient by means such as the injection of thymus gland extracts into elderly animals, there has certainly been a rejuvenating effect, but there is no evidence of increased life span. As Weindruch and Walford put it: ‘As part of the life extension induced by dietary restriction the immune system is kept “younger” longer by a mechanism whose ultimate origin lies elsewhere.’

Overview

So, how does dietary restriction influence life extension? Despite heroic research our understanding of the aging process remains only partial, with extremely strong views being held as to the relative importance of one or other aspect of it. The influence of dietary restriction on all of the various contenders for the ‘major’ influence on aging seems to make it a universally applicable technique, whether we are looking at how cells function in terms of self-repair and protein synthesis; or energy production and use; or the influence of the immune and endocrine (hormonal) systems; or the build up of altered structures (cross-linkage) and toxins, often related to free radical activity.

It might well be that aging is the result of a decline in efficiency brought about by wear and tear, a gradual overload which our self-repairing mechanisms ultimately fail to deal with. Or aging might be the result of a built-in obsolescence factor, or indeed it might be the result of a combination of these and other as yet unidentified elements.

Whatever the causes of ageing, and their inter-connection with one another, dietary restriction seems to have the ability to improve protective mechanisms, to enhance protein synthesis and DNA (and other) self-repair mechanisms, to encourage a more efficient use of energy and to improve both hormonal and immune functions.

Whether it is the cells or the environment which produce
ageing, life extension is possible via this simple technique, either by making the cells more efficient or by improving our ability to deal with the environment. Infinite life extension is clearly impossible, but the achievement of what is possible is easier via dietary restriction.

Are there other ways? Some people think so, and I now explain some of these.